Yale's Inzucchi Reviews Array of Choices for Matching Patients With Therapies

A generation ago, there were few therapeutic choices for physicians trying to manage a patient’s type 2 diabetes mellitus (T2DM). As Silvio E. Inzucchi, MD, described it, there was insulin, and there were sulfonylureas, and “That was essentially it.”

Then came metformin in 1995,¹ which transformed diabetes care, followed by a new class of therapy every 2 to 3 years, according to Inzucchi, professor of medicine and director of the Yale Diabetes Center. His April 16, 2015, talk at Patient-Centered Diabetes Care 2015, “Personalizing Diabetes Care: Matching Patients and Therapies,” logically followed the discussion of how to motivate patients: tailoring treatment depends, in part, on what each person can handle in terms of risk, side effects, adherence, and other factors.

Inzucchi spoke to the multistakeholder gathering convened in Boston by The American Journal of Managed Care and Joslin Diabetes Center.

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The arrival of so many choicesthere are now 12 individual drug classes to treat hyperglycemia and T2DMhas meant “both good news and bad news,” Inzucchi said. “We can individualize therapy, but the bad news is that it’s become awfully confusing to put these medications together.” He described the “noise” from both the clinical world and the media about safety issues, which can evolve from the issues surrounding the challenge of tailoring care to individuals.

The question of how tightly to control a patient’s glycated hemoglobin (A1C) depends on clinical factors such as age, comorbidities, and how long they have had T2DM, but also on their feelings about the disease or even what type of work they do. An episode of hypoglycemia that causes a person to pass out is potentially more dangerous for an electric line worker, for example, than for someone who sits behind a desk.

Inzucchi also discussed the 2015 Standards of Medical Care in Diabetes, published in January by the American Diabetes Association (ADA),² as well as the related update to the position statement from the ADA and European Association for the Study of Diabetes (EASD) on the management of hyperglycemia,³ of which he was the lead author.

As shown in the ACCORD trial,⁴ he said, too-tight glucose control “might actually do more harm than good in those patients with preestablished cardiovascular disease.”

The bigger challenge, he said, is understanding each individual’s circum-stances. Some patients are unmotivated and will not embrace self-care. Others are motivated, but suffer multiple comorbidities that make prescribing mul-tiple therapies just for T2DM a judgment call. This, he said, is the “the art of medicine.” Physicians have to weigh each patient’s entire situation when deciding how strictly they want to manage A1C.

Metformin remains the foundation, he said. “It’s the most commonly pre-scribed diabetes medication in the United States actually, in the world. It reduces blood glucose by targeting hepatic glucose production; it actually decreases the amount of glucose the liver makes.” Because it is not associated with hypoglycemia, it offered huge advantages over insulin and sulfonylureas when it arrived 20 years ago. Today, metformin is very cost-effective, too. But over time, it is often necessary to add another ther-apy to keep A1C in check, Inzucchi said. And that’s where clinical judgment, pa-tient preferences, and cost factor in.

THIAZOLIDINEDIONES.

Also called TZDs, these were popular in the mid-2000s, Inzucchi said, but they fell out of favor after side effects emerged over a decade of clinical trials. (The FDA required a leading TZD, rosiglitazone, to be sold with restrictions starting in November 2011, only to lift them in 2013. Its patent expired in 2012.⁵) Inzucchi noted that TZDs are available in generic form, are cost-effective, and are “most durable because they off-load the pancreatic beta cells.”

DIPEPTIDYL PEPTIDASE 4 INHIBITORS.

Inhibitors of DPP-4 activate the incretin system and are not associated with hypoglycemia, Inzucchi said. He discussed the issue with saxagliptin before the FDA; days before Inzucchi’s talk, an FDA advisory committee recommended changing the label to indicate that the therapy may increase heart risk.⁶ (On April 27, 2015, Merck released top-line data from a study indicating that its competing DPP-4 inhibitor, sitagliptin, did not carry the same hospitalization risk as saxagliptin. At press time, full results were scheduled to be presented at the 75th Scientific Sessions of the ADA on June 8, 2015.⁷)

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS.

The SGLT2 inhibitors work by increasing the amount of glucose excreted through the urine; “a bizarre mechanism of action,” Inzucchi terms it, “but it does tend to work.” Studies are showing that this class also decreases blood pressure^.8 Because the mechanism of action does not require beta cell function, the value of SGLT2 inhibitors for patients with type 1 diabetes mellitus (T1DM) is being studied, he said. The chief side effect is genitourinary infection.

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS.

These injectable drugs, GLP- 1 receptor agonists, are activators of the incretin system. “They decrease body weight. They’re not associated with hypoglycemia,” Inzucchi said. The challenge here is that some patients resist an injectable medication, and there are also concerns about pancreatitis. The other barrier which also exists with DPP-4 and SGLT2 inhibitors is the cost, because all these drugs are branded.

INSULIN

The original treatment for T1DM and T2DM has been around for nearly a century. Insulins, Inzucchi said, “have unlimited efficacy, but their downside is obviously hypoglycemia, weight gain, and the fact that they’re injectable although there’s a new inhaled version that was recently released (Afrezza⁹) so there are more significant training requirements here in terms of safe administration…and the costs are extremely variable.” Older insulins that are off patent can be cost-effective, but newer branded versions which may be more long-acting can be expensive.

“I guess the point here is that we do have lots of different treatment options. They’re each targeted at one or more of the pathophysiological defects in type 2 diabetes,” he said. “Just like it’s important to individualize the treatment tar-get in a patient, it’s critically important to try to match the drug to the patient in terms of not only pathophysiology, effi-cacy, but also side effect profiles.”

In selecting the right medications, he urged consideration of what he called the “5 Ps,” which are “the pathophysiol-ogy of the person’s diabetes, the potency of the drug that you need, the various precautions or side effects from those medications, other practicalities of care, and perks or perquisites.” In other words, he advised, consider the “added benefits from these medications.”

Later, Inzucchi conceded there is a sixth “P,” which is “price.”

For all the therapy options available, however, Inzucchi said the recent posi-tion statement from the ADA and the EASD found that the backdrop for all dia-betes therapy should be lifestyle change, since only about 10% to 15% of T2DM patients have normal body weight.

“The genesis of type 2 diabetes, some would say, starts with obesity,” he said. “That increases insulin resistance, and we’re not going to talk about the patho-genesis of diabetes, but it’s felt by most of the people who study this that obesity is really one of the cardinal, fundamental defects that leads to insulin resistance and, eventually, beta cell failure.”

References

1. Generic Glucophage availability. Drugs.com website. http://www.drugs.com/availability/ge-neric-glucophage.html. Accessed May 16, 2015.

2. American Diabetes Association. Standards of medical care in diabetes—2015. Diabetes Care.2015;38(suppl 1):S1-S93.

3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. Diabetes Care. 2015;38:140-149.

4. Skyler JS, Bergenstal RM, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials. Diabetes Care. 2009;32(1):187-192.

5. Regan TL. FDA “Mea culpa” part of cautionary tale. Am J Manag Care. 2013;19(SP7):S242-SP243.

6. Staton T. Onglyza label should flag heart failure risk, FDA panel says. FiercePharma website. http://www.fiercepharma.com/story/onglyzas-label-should-flag-heart-failure-risks-fda-panel-says/2015-04-14. Published April 14, 2015. Accessed April 20, 2015.

7. Edney A. Merck gains as Januvia diabetes drug doesn’t add to heart risk. Bloomberg website. http://www.bloomberg.com/news/ articles/2015-04-27/merck-gains-as-januvia-di-abetes-drug-doesn-t-add-to-heart-risk. Published April 27, 2015. Accessed May 16, 2015.

8. Smith A. Studies are showing SGLT2s also help control hypertension, eliminate some side effects. Am J Manag Care. 2015;21(SP5):SP156-SP157.

9. Smith A. Toujeo and Afrezza: new and im-proved insulins, limited by FDA labeling con-straints. Am J Manag Care. 2015;21(SP7):SP226-SP227.